Abstract：
Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) and histone deacetylase 8 (HDAC8) have been shown to be associated with the development of several cancers. Here, we identified a dual-target DYRK2/HDAC8 inhibitor (DYC-1) through a combined virtual screening protocol. DYC-1 exhibited nanomolar inhibitory activity against both DYRK2 (IC50 = 5.27 ± 0.13 nM) and HDAC8 (IC50 = 8.06 ± 0.47 nM). Molecular dynamics simulations showed that DYC-1 had positive binding stability with DYRK2 and HDAC8. Importantly, the cytotoxicity assay indicated that DYC-1 exhibited superior antiproliferative activity against human liver cancer, especially SK-HEP-1 cells, and had no significant inhibition on normal liver cells. Moreover, DYC-1 showed a strong inhibitory effect on the growth of SK-HEP-1 xenograft tumors with no significant side effects. These data suggest that DYC-1 is a high-efficacy and low-toxic antitumor agent for the treatment of hepatocellular carcinoma.
摘要：
双特异性酪氨酸磷酸化调节激酶2（DYRK2）和组蛋白脱乙酰酶8（HDAC8）已显示与几种癌症的发展有关。这里,我们通过联合虚拟筛选方案鉴定了双靶点DYRK2/HDAC8抑制剂(DYC-1).DYC-1表现出对DYRK2(IC50=5.27±0.13nM)和HDAC8(IC50=8.06±0.47nM)的纳摩尔抑制活性。分子动力学模拟显示DYC-1与DYRK2和HDAC8具有正的结合稳定性。重要的是,细胞毒性实验表明DYC-1对人肝癌具有优越的抗增殖活性，尤其是SK-HEP-1细胞,对正常肝细胞无明显抑制作用。此外，DYC-1对SK-HEP-1异种移植瘤的生长表现出较强的抑制作用,且无明显副作用。这些数据表明DYC-1是用于治疗肝细胞癌的高效低毒性抗肿瘤剂。
